Alternative Therapies for Chemotherapy-Induced Peripheral Neuropathy

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect caused by many antineoplastic drugs. Currently, there are no FDA-approved drugs for CIPN management. Substantial and accumulating clinical and preclinical evidences show that alternative and complementary therapies may provide promising efficacy on the management of CIPN. In this chapter, we will summarize the current clinical and preclinical application of alternative and complementary therapies in alleviating CIPN symptoms, including acupuncture, medicinal herbs, exercise, cryotherapy, massage, and photobiomodulation. In the end, we will briefly comment on several problematic issues in the studies of alternative and complementary therapy for CIPN and present a prospective view in terms of future research to improve the clinical application of alternative and complementary therapy to make it more beneficial to patients.

1 Introduction

Currently, cancer has emerged as the leading cause of death and an important barrier to increasing life expectancy in the world (Bray et al. 2021; Sung et al. 2021). According to GLOBOCAN estimates, there are approximately 19.3 million new cancer cases and almost 10.0 million cancer deaths occurred in 2020 worldwide (Sung et al. 2021), which are higher than in 2018 (Bray et al. 2018). However, cancer mortality rates are declining due to the improvements in combating cancer through preventive intervention, early detection, and treatment (Wild et al. 2020). Chemotherapy, one of the major approaches used for cancer treatment in clinic, is a therapy by using chemical agents to treat diseases, especially to treat cancers, by administration of one or more cytotoxic agents to inhibit or destroy the growth and division of malignant cells. It often induces severe side effects and directly affects the quality of life of patients. The side effects include cardiotoxicity, hepatotoxicity, renal toxicity, neurotoxicity, and so on (Xiao et al. 2018; Liu et al. 2021).

Chemotherapy-induced peripheral neuropathy (CIPN), a common side effect caused by many chemotherapeutic agents, has received wide attention for its significant dose-limiting side effect during chemotherapy. To date, no FDA-approved drugs have been invented to prevent this toxicity (Wolf et al. 2008). It has even been reported as irreversible (Wadia et al. 2018). These chemotherapeutic agents include platinum-based drugs (e.g., carboplatin, cisplatin, and oxaliplatin), taxanes (e.g., paclitaxel and docetaxel), epothilones (e.g., ixabepilone), vinca alkaloids (e.g., vincristine and vinblastine), thalidomide, and bortezomib (Brewer et al. 2016). According to the National Cancer Institute, annually 165,544 patients survive cancer in the UK and 1 million in the USA (Seretny et al. 2014), while the CIPN rates were reported ranging from 19% to more than 85% (Fallon 2013). The cancer patients receiving antineoplastic treatments experience a characteristic set of symptoms including severe pain in a symmetrical stocking and glove distribution on hand and feet (Boyette-Davis et al. 2011b), along with sensory abnormities like numbness, dyskinesia, and tingling, which were described as burning, shooting, throbbing, and stabbing (Boyette-Davis et al. 2015; Kaley and Deangelis 2009). These symptoms are aggravated with cumulative antineoplastic treatments and might be permanent (Mielke et al. 2006; Leblanc et al. 2018) with the disruption of physical abilities and the reduction of the quality of life (Cavaletti et al. 2008). For example, according to an evaluation of the impact of CIPN on breast cancer survivors, more than 50% of patients experiencing chemotherapy have disruption of work ability, combining discomfort, numbness, and tingling in their hands and feet approximately 1 year later (Zanville et al. 2016). Thus, cancer patients frequently suffer from progressing, enduring, often irreversible, and dose-limiting nerve damage during chemotherapy. Unfortunately, there are no established therapeutic strategies for the management of chemotherapy-induced peripheral neuropathy.

2 Understanding of CIPN

Although the pathogenesis of CIPN has been studied for decades, the mechanism of CIPN still has not been completely understood. Accumulated evidences indicate that the initiation and progression of CIPNs are tightly related to chemotherapeutic agent-induced loss of intraepidermal nerve fibers (IENFs), oxidative stress, abnormal spontaneous discharge, ion channel activation, the upregulation of various pro-inflammatory cytokines, and the activation of the neuro-immune system (Fig. 1) (Hu et al. 2019). Based on these findings, an abundance of pharmacological and nutraceutical agents has been developed to prevent and treat CIPN by protecting nerve impairments, blocking ion channels, targeting inflammatory cytokines, and combating oxidative stress (Fig. 1). These agents include acetyl-L-carnitine (Flatters et al. 2006), Ca/Mg (Cavaletti 2011), allopregnanolone (Meyer et al. 2011), 3α-androstanediol (Meyer et al. 2013), poly(ADP-ribose) polymerase inhibitor (Ta et al. 2013), omega-3 fatty acids (Ghoreishi et al. 2012), amifostine, glutamine, glutathione, oxcarbazepine, venlafaxine, duloxetine (Brewer et al. 2016; Schloss et al. 2013; Argyriou et al. 2014; Brami et al. 2016; Smith et al. 2013), etc. For instance, according to a case report, a 68-year-old man with gastric cancer obtained remission of his symptoms induced by paclitaxel following treatment with a combination of duloxetine and pregabalin (Takenaka et al. 2013). However, though the current effective mechanism-based therapeutics such as glutathione and mangafodipir appear to be promising or to be expected to be effective for CIPN prevention or treatment, there are no FDA-approved drugs for CIPN treatment (Hu et al. 2019).

Fig. 1

Mechanism-based therapeutics for chemotherapy-induced peripheral neuropathy

According to the theory of traditional Chinese medicine, sensory neuropathy belongs to Bi (arthralgia) syndrome, which includes numbness of the four limbs, no feeling of pain and itching, and dyskinesia in movement (Li et al. 2006). Chemotherapy-induced peripheral neuropathy is primarily caused by abnormalities in the flow of “blood” and “qi.” Essentially, blood is the substance that nourishes the tissues, and qi moves the blood to the tissues. CIPN causes the body not to send the blood to the limbs (qi) and leads to nourishment deficiency of the muscles (blood). The use of complementary and alternative medicines by the patients undergoing chemotherapy is increasing (Lu et al. 2017). More and more studies reported that complementary and alternative medicines may have beneficial effects on preventing or reducing CIPN symptoms. It includes acupuncture, herbal medicine, massage, as well as exercise, cryotherapy, and other complementary therapies (Derksen et al. 2017).

3 Alternative Therapies for CIPN

In the following section, we will summarize the clinical application as well as animal studies of alternative therapies, which showed a promising benefit on CIPN management. These alternative therapies include acupuncture, herbal medicine, massage, exercise, cryotherapy, and others.

3.1 Acupuncture Therapy

As an important part of traditional Chinese medicine, acupuncture is an ancient form of treatment that originated in China, which has been practiced for over 2000 years. It is a nondrug treatment for regulating body homeostasis by inserting needles into specific acupoints, which are richly innervated by peripheral nerves, of the human body. In the theory of traditional Chinese medicine, there are several patterns of qi flowing throughout the body, and stagnation of qi leads to illness. Qi is defined as matter + energy or “mattergy,” indicating something that is simultaneously material and immaterial and expressing the continuum of matter and energy as explained by modern particle physics (Zhou et al. 2009). Acupuncture dissolves illness by promoting qi stagnation. In modern biomedical nomenclature, needling of the acupoints activates the afferent fibers of peripheral nerves and the nerve-mediated signals ascend to various levels of the central nervous system subsequently (Hsiang-Tung 1978; Zhao 2008; Torres-Rosas et al. 2014). Therefore, proposed putative mechanisms of acupuncture involve the regulation of the nervous system, immune system, and alteration of biochemical substance, such as neurotransmitters, hormones, etc.

Numerous clinical and preclinical reports have proved the promising analgesic effect of acupuncture in many kinds of chronic pain conditions, such as neuropathic pain, inflammatory pain, and certain kinds of cancer pain. In White Paper 2017, acupuncture was recommended as a first-line treatment for pain management (Fan et al. 2017). The World Health Organization recommends acupuncture to treat more than 100 diseases, including adverse reactions to radiotherapy and/or chemotherapy, and several pain conditions. It is considered as one of the most effective alternative medical treatment with the advantages of low cost, simple application, and minimal side effects in pain management. Acupuncture has shown promise as a treatment option for CIPN. In the following section, acupuncture application in CIPN prevention or treatment is demonstrated with respect to different forms of acupuncture. Table 1 shows the acupoints used in clinical trials of acupuncture for CIPN.

Table 1 Acupoints used in clinical trials of acupuncture for CIPN

3.1.1 Manual Acupuncture

Manual acupuncture is the most common type of acupuncture therapy with a very long practice history in China. Acupuncture needles are inserted into the selected acupoints, and the depth of needling varies based on the acupoints’ location and the patient’s body size (Lu et al. 2020). Except for the acupoints, the therapeutic effects of manual acupuncture are closely related to achieving the acupuncture feeling or de-qi sensation as well as the intensity of the acupuncture feeling (Maoying and Mi 2010). The acquisition of acupuncture feeling depends on certain manipulation, such as lifting, thrusting, twisting, and twirling the needles. Acupuncture feeling or de-qi sensation is defined as the acupuncturist feeling a tugging or grasping sensation from needle manipulation and the patient feeling soreness, numbness, heaviness, or distention (Lu et al. 2020). The effects of acupuncture with different manipulation on CIPN were conducted in different clinical trials.

• 1. Manipulation when inserting needles. In a pilot, randomized, assessor-blinded, controlled trial, the effectiveness of manual acupuncture treatment on chemotherapy-induced peripheral neuropathy was evaluated (Iravani et al. 2020). Forty patients with CIPN were randomly assigned to acupuncture or vitamin B1 and gabapentin treatment group. The results showed that manual acupuncture treatment is significantly effective in the treatment of CIPN in Numerical Rating Scale, National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), sensory neuropathy grading scales, and nerve conduction study. Moreover, acupuncture is more effective than using vitamin B1 and gabapentin (300 mg of vitamin B1 and 900 mg of gabapentin per day for 4 weeks) as the conventional treatment. In this trial, acupuncture needles were inserted into acupoints with proper manipulation to induce de-qi and then retained for 20 min. Acupuncture treatment was implemented three times per week for 4 weeks.

• 2. Manipulation when inserting and before removing needles. In another randomized assessor-blinded wait-list-controlled trial, acupuncture needles were rotated just after inserting the needle and before removing the needle to sustain acupuncture sensation (Molassiotis et al. 2019). After the treatment with acupuncture twice a week for 8 weeks, it showed an effective intervention for treating CIPN compared to the standard care control that received pain medication, vitamin B₁₂/B₆, or other medication deemed necessary by the doctor.

• 3. Gentle manipulation without needle sensation. A pilot trial of ten patients suffering from peripheral neuropathy after taxane chemotherapy for breast cancer showed that gentle acupuncture treatment improved CIPN (Jeong et al. 2018). In this trial, acupuncture needles were gently inserted into acupoints to attain de-qi and were gently rotating without needle sensation 10 min after insertion.

• 4. Acupuncture without much needle manipulation. A retrospective case series of ten patients who were undergoing oxaliplatin-induced peripheral neuropathy also showed that ten patients had considerable improvement with respect to prevention and mitigation of CIPN-associated symptoms after acupuncture treatment without much manipulation (Valentine-Davis et al. 2015). It is known that patients undergoing chemotherapy tended to be in a mostly deficient condition and did not require much needle manipulation.

3.1.2 Electroacupuncture

Electroacupuncture (EA) is a modern form of acupuncture, which is a combination of acupuncture and electrical stimulation. It has been widely used in China for decades. To attain the acupuncture sense, little electrical current is applied to the acupoints to enhance the acupuncture effects, by connecting the acupuncture needles to an EA apparatus. Besides the selected acupoints, the effect of EA varies from the different wave forms, pulse frequency, intensity, pulse width, and duration of the electrical stimulation. For example, low-frequency electrical stimulation releases endorphin and enkephalin, while high-frequency stimulation releases dynorphin (Han et al. 1991; Maoying and Mi 2010). Alternating sparse-dense frequency, which is composed of high and low frequencies, has synergistic effects on chronic pain and may facilitate synaptic remodeling to pre-pain-activated microanatomy (Maoying and Mi 2010; Zhou et al. 2009).

In a single-blinded randomized controlled trial of 38 patients with malignant tumor, the patients received acupuncture or electroacupuncture once per day starting at the day before chemotherapy for 7 consecutive days followed by 14 days off, with 21 days as a course of treatment (Zhang et al. 2017). For EA treatment, needles were inserted to acupoints and stimulated manually to attain de-qi, and then the electrical stimulation was applied by attaching the needles to an electrical stimulator. The patients receiving acupuncture also underwent the same operation as EA, but without electrical stimulation. After two courses of acupuncture treatment, the patients receiving EA treatment had lower incidence of peripheral neuropathy than those receiving acupuncture treatment. Another feasibility study of 19 patients with neuropathy also suggested that EA may help the patients experiencing chemotherapy-induced peripheral neuropathy (Garcia et al. 2014). However, there are clinical trials showing no significant improvement of CIPN by EA treatment compared to sham EA control (sham acupoint and needles touch but do not penetrate the skin), vitamin B, or placebo treatment (Greenlee et al. 2016; Rostock et al. 2013).

3.1.3 Pharmacopuncture/Acupoint Injection

Pharmacopuncture, also named acupoint injection, is a special technique of a combination of acupuncture and injection. It involves the injection of pharmaceutical derivatives into acupoints and has dual function of acupuncture and drug therapy. It is commonly used in traditional oriental medicine. In a clinical study of patients undergoing CIPN with breast cancer, 29 patients received pharmacopuncture of 0.1 mL of mecobalamin (an indispensable coenzyme of methyltransferase able to repair damaged nervous tissues and to improve conducting function) into each acupoint. The results showed that acupoint injection with mecobalamin can improve the nerve conduction velocity of the patients (Zhi-feng et al. 2016). The effect of pharmacopuncture on CIPN was also supported by two additional case reports by injecting melittin (the pharmacological component in sweet bee venom which is reported to have analgesic, anti-inflammatory, and anticancer effects) into acupoints (Park et al. 2012b; Yoon et al. 2012).

3.1.4 Laser Acupuncture

Laser acupuncture (LA) is a technique of noninvasive somatosensory stimulation by applying laser energy on acupoints with the advantage that the skin does not need to be punctured. It has been demonstrated that LA significantly reduces many chronic pain conditions, such as neuropathic pain in patients with carpal tunnel syndrome, low back pain, chronic knee pain, pain due to plantar fasciitis, and so on. It is currently being used for a wide range of different conditions. In a pilot prospective cohort study of 17 patients undergoing oxaliplatin-induced peripheral neuropathy with gastrointestinal cancer, the patients received LA treatment three times per week for 4 consecutive weeks (Hsieh et al. 2016). LA treatment was administered by a laser system with a wavelength of 780 nm at 100 Hz. LA spot size was approximately 0.2 cm², and output power was 80 mW per session. The results showed that LA treatment significantly reduced oxaliplatin-induced cold and mechanical allodynia and reduced the incidence and severity of neurotoxicity symptoms of the patients. It indicates that LA treatment is able to improve the CIPN of cancer patients and may be an effective noninvasive strategy for CIPN. Further rigorously controlled, larger-scale, long-term trials are needed to evaluate the role of LA as a therapeutic option in the management of CIPN.

3.1.5 Ultrasound Acupuncture

Like laser acupuncture, ultrasound acupuncture (UA) treatment is also a noninvasive technique by applying pulsed therapeutic ultrasound at the acupoints. Ultrasound acupuncture provides localized mechanical and thermal stimulation to acupoints to elicit de-qi sensation. It has been proposed as a feasible alternative to traditional needle acupuncture. Ultrasound acupuncture is used to accelerate the recovery of injured nerves and to manage pain by modulating the function of peripheral nerves. The effect of ultrasound acupuncture on chemotherapy-induced peripheral neuropathy has been demonstrated both in clinic and animal study (Chien et al. 2021; Hsieh et al. 2017). In a recent pilot study, ultrasound acupuncture was applied to acupoints of patients for 5 minutes per day for a total of 12 treatments. After ultrasound acupuncture, the touch detection threshold was significantly decreased and cold pain withdrawal latency was significantly increased. Furthermore, the scores of Pain Quality Assessment Scale (PQAS) and Chemotherapy-induced Neurotoxicity Questionnaire (CINQ) were significantly increased. All these indicate ultrasound acupuncture could be an effective intervention for CIPN.

3.2 Herbal Medicines

Herbal medicines have been widely used in oriental medicine, especially in traditional Chinese medicine. The forms of herbal medicines include herbal formulation, single herb, and active component. The biological ingredients of herbal medicines are mainly extracted from plants, animals, stones, and minerals. In recent decades, numerous basic and clinical studies have been conducted to identify the effects of herbal medicines including herbal formulations, single herb, and active component on the management of chemotherapy-induced peripheral neuropathy. It is widely believed that herbal medicines contain a number of active compounds with the main problem of uncovering mechanism; nevertheless, herbal medicines could still provide an accelerated path to overcome obstacles to the alleviating of CIPN in clinical applications. Many promising substances identified from medical herbs might deal with multiple targets for neuroprotection or neuroregeneration in CIPN (Schroder et al. 2013). Here, we summarized the current researches of herbal medicines in CIPN management.

3.2.1 Herbal Formulation

Herbal formulations (Kampo in Japanese) are a combination of several herbs in relative-fixed dosages. Currently, several herbal formulations, such as Niuche Shenqi Wan (Goshajinkigan), Huangqi Guizhi Wuwu Tang, Shaoyao Gancao Tang (Shakuyaku-Kanzo-to), Guilong Tongluo Fang, and Renshen Yangrong Tang (ninjin’yoeito), have been found to have a potential effect in preventing or treating chemotherapy-induced peripheral neuropathy. A brief outline of the beneficial effect of some herbal formulations for CIPN management in clinic or in animal is presented below (Tables 2 and 3).

Table 2 Clinical studies of herbal formulations in the management of chemotherapy-induced peripheral neuropathy

Table 3 Preclinical studies of herbal formulation in the management of chemotherapy-induced peripheral neuropathy

3.2.1.1 Niuche Shenqi Wan (Chinese)/Goshajinkigan (Japanese)/Jesengsingi-Hwan (Korean)

Niuche Shenqi Wan , a traditional Chinese herbal medicine, named from “Jisheng Fang” in the Song dynasty, was widely used in treating nephritis, hypertension, diabetes mellitus, sciatica, and so on (Schroder et al. 2013; Chen et al. 2018). This formula contains ten herbs including Rehmannia viride radix, Achyranthis bidentatae radix, Corni fructus, Dioscorea opposita rhizome, Plantaginis semen, Alismatis rhizome, Moutan cortex, Cinnamomi cortex, Aconiti lateralis praeparata radix, and Poria alba (Chen et al. 2018). Niuche Shenqi Wan is also known as Goshajinkigan (GJG) in Japanese or Jesengsingi-Hwan in Korean, which has been frequently used for alleviating the symptoms such as numbness, cold sensation, and paresthesias/dysesthesias of diabetes-induced peripheral neuropathy (Oki et al. 2015; Kono et al. 2013; Schloss et al. 2017; Wu et al. 2019a). In a phase 2, randomized, double-blind study, the effect of GJG in protecting against the neurotoxicity of chemotherapy was evaluated. Trials on humans conducted on this formula showed that the concomitant administration of GJG reduced the oxaliplatin-induced peripheral neurotoxicity in patients who received chemotherapy for colorectal cancer (Kono et al. 2011). A multicenter study also showed that GJG alleviated the paclitaxel/carboplatin-induced peripheral neuropathy in patients with ovarian or endometrial cancer who underwent chemotherapy and developed peripheral neuropathy (Kaku et al. 2012). The effects of GJG in prevention of CIPN have been reported by several other clinical studies (Oki et al. 2015; Yoshida et al. 2013; Abe et al. 2013; Nishioka et al. 2011; Kono et al. 2013).

The animal studies showed that GJG could reduce the paclitaxel- or oxaliplatin-induced mechanical allodynia in rodents (Bahar et al. 2013; Matsumura et al. 2014; Kato et al. 2014; Ushio et al. 2012; Kono et al. 2015; Mizuno et al. 2016). On one side, the descending noradrenergic and serotonergic systems, as well as κ-opioid receptor, are considered to be involved in the effect of GJG on chemotherapy-induced mechanical allodynia (Andoh et al. 2014; Ushio et al. 2012). On the other side, GJG might exert its effect by preventing degeneration of the ganglion cells and suppressing transient receptor potential vanilloid 4 (TRPV4) in the dorsal root ganglia (DRG) (Matsumura et al. 2014). In addition, GJG could reduce oxaliplatin-induced cold allodynia and hyperalgesia by suppressing functional alteration of transient receptor potential (TRP) channels, especially transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential melastatin 8 (TRPM8) (Kato et al. 2014). Furthermore, GJG could attenuate the oxaliplatin-induced generation of reactive oxygen species (Kono et al. 2015). And GJG prevented chemotherapy-induced peripheral neuropathy without interfering with the anticancer action of paclitaxel and oxaliplatin (Bahar et al. 2013; Ushio et al. 2012). However, GJG has been reported not to prevent the oxaliplatin-induced axonal degeneration in the rat sciatic nerve, although it inhibits oxaliplatin-induced allodynia (Ushio et al. 2012).

3.2.1.2 Shaoyao Gancao Tang (Chinese)/Shakuyakukanzoto (Japanese)/Jakyakgamcho-Tang (Korean)

Shaoyao Gancao Tang, named Shakuyakukanzoto in Japanese or Jakyakgamcho-Tang in Korean, is an extract of a mixture of glycyrrhiza and peony root, composed with Paeoniae radix and Glycyrrhizae radix (Chen et al. 2018; Schroder et al. 2013; Schloss et al. 2017; Wu et al. 2019a). It has been reported to be effective against muscle pain, muscle spasms, joint pain, numbness, and paclitaxel-induced peripheral neuropathy (Yoshida et al. 2009). It has anticholinergic and prostaglandin production-inhibiting actions. A multicenter retrospective study shows that only seven patients occurred grade 1–2 toxicity in 24 patients with metastatic colorectal cancer received 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX) after they concurrently received Shakuyakukanzoto for neurotoxicity reduction (Hosokawa et al. 2012). The administration of Shakuyakukanzoto might reduce oxaliplatin-induced neurotoxicity without negatively affecting tumor response in patients.

The effect of Shakuyakukanzoto on chemotherapy-induced peripheral neuropathy was also evaluated in a mouse model of oxaliplatin- or paclitaxel-induced peripheral neuropathy (Andoh et al. 2017b; Hidaka et al. 2009). Shakuyakukanzoto significantly relieved the allodynia and hyperalgesia induced by paclitaxel. In contrast, partially mild pain-killing effect was shown after a single administration of Shakuyaku (Shaoyao) or Kanzo (Gancao), but not significant (Hidaka et al. 2009). It is worth mentioning that those effects were based on the synergy between Shakuyaku and Kanzo, which demonstrated the significance of synergistic effects and provided a rationale for the herbal combinations. In addition, the prophylactic effect of repetitive Shakuyakukanzoto administration in preventing the exacerbation of oxaliplatin-induced cold dysesthesia is by inhibiting the mRNA expression of TRPM8 in the dorsal root ganglia (Andoh et al. 2017b).

3.2.1.3 Huangqi Guizhi Wuwu Tang (AC591 Preparation)/Ogikeishigomotsuto (Japanese)

Huangqi Guizhi Wuwu Tang was first described in the book “Synopsis of the Golden Chamber” (named Jingui Yaolue in Chinese) written by Zhang Zhongjing at the beginning of the third century for treating numbness, vibration sensation, cold sensation, and limb ache (Cheng et al. 2017; Gu et al. 2020). It is composed of Astragali radix (Huangqi), Cinnamomi ramulus (Guizhi), Paeonia radix alba (Shaoyao), Jujubae fructus (Dazao), and Zingiberis rhizoma (Shengjiang) at a ratio of 2:1:1:1:1. Similar composed formulation is called Ogikeishigomotsuto in Japan (Schloss et al. 2017). Astragali radix is used for invigorating qi, Cinnamomi ramulus is for activating yang, Paeonia radix alba is for nourishing blood, and Jujubae fructus is for harmonizing yin and yang. Huangqi Guizhi Wuwu Tang is mainly used for the hand-foot syndrome, CIPN, diabetic peripheral neuropathy, and rheumatoid arthritis. AC591 is a standardized extract from Huangqi Guizhi Wuwu Tang (Chen et al. 2018). It has been reported to lower the incidence and reduce the severity of neurotoxicity of patients undergoing chemotherapy. In a study of 72 colorectal cancer patients with undergoing oxaliplatin chemotherapy (Cheng et al. 2017), the lower percentage of grades 1–2 neurotoxicity was reported in AC591-treated patients (25%) than in the non-AC591-treated patients (55.55%) after four cycles of AC591 treatment (54 g crude drug per day). Moreover, there were no significant differences in the tumor response rate between AC591- and non-AC591-treated patients. The study indicated that AC591 can prevent oxaliplatin-induced neuropathy without reducing its antitumor activity. The effect of AC591 in preventing CIPN was further demonstrated in a rat model of oxaliplatin-induced peripheral neuropathy (Cheng et al. 2017). The results showed that pretreatment with AC591 reduced oxaliplatin-induced cold and mechanical allodynia as well as morphological changes of dorsal root ganglia. Further analysis indicated that the neuroprotective effect of AC591 may depend on the modulation of multiple molecular targets and pathways in dorsal root ganglion involved in the downregulation of inflammation and immune responses. The analysis by network pharmacology also shows that AC591 plays a therapeutic effect in CIPN management by regulating inflammatory response and repairing nerve injury (Gu et al. 2020).

Based on Huangqi Guizhi Wuwu Tang, Radix angelicae sinensis, Caulis spatholobus, ground beetle, Radix paeoniae rubra, and Herba siegesbeckiae were added into Jiawei Huangqi Guizhi Wuwu Tang. In a randomized controlled self-crossover trial of 31 patients undergoing oxaliplatin treatment (Li et al. 2006), 64.5% of patients suffered from neurosensory toxicity (mainly cold-induced paresthesia) in Jiawei Huangqi Guizhi Wuwu Tang-treated patients and 87.1% in the control group. Furthermore, the symptoms were more serious and lasted longer in the control group than those in the treated group. The study suggested that Jiawei Huangqi Guizhi Wuwu Tang could prevent and reduce the incidence and intensity of oxaliplatin-induced peripheral neuropathy.

3.2.1.4 Chinese Herbal Compound LC09

LC09 is composed of Astragalus membranaceus (30 g) , flowers carthami (12 g), Lithospermum (20 g), Geranium wilfordii (30 g), and Radix angelicae (18 g). It is boiled directly into decoction and is usually applied externally by soaking the affected hands and feet in the decoction for treating hand-foot syndrome (HFS)-related pain. In a randomized, double-blind, and parallel-controlled trial of 156 patients with HFS (Yu et al. 2020), the treatment group received LC09 treatment while the control group received low-dose herbs in a concentration of about 5% with 95% starch. Low-dose herbs in control group included Rehmannia glutinosa, Rhizoma alismatis, garden burnet, and calamus, which are not effective for HFS according to traditional Chinese medicine. The results show that LC09 can significantly alleviate pain induced by capecitabine. Furthermore, it can also increase chemotherapy completion rate without adverse reactions.

In addition, clinical trials showed that Guilong Tongluo Fang and Renshen Yangrong Tang (ninjin’yoeito in Japanese) displayed promising effect in reducing the incidence of oxaliplatin-induced peripheral neuropathy in patients with colorectal cancer undergoing oxaliplatin chemotherapy (Motoo et al. 2020; Liu et al. 2013). Furthermore, several other herbal formulations, such as Bawei Dihuang Wan, Siwei Jianbu Tang, Wenluotong Tang, etc., have been evaluated to be effective in preventing or treating chemotherapy-induced peripheral neuropathy in preclinical animal studies (Table 3).

3.2.2 Single Herbs

In this section, we will choose some single herbs that had been confirmed to be effective in CIPN management and give a brief introduction regarding clinical and preclinical studies.

3.2.2.1 Radix Astragali

Radix astragali (Huangqi in Chinese) is one of the most famous and frequently used herbs to treat qi deficiency according to the traditional Chinese medicine theory (Chen et al. 2018). It is an important component of Huangqi Guizhi Wuwu Tang. The chemical composition of Radix astragali includes triterpenoid saponins, polysaccharides, flavonoids, amino acids, and trace elements (Wang et al. 2018). Multiple randomized clinical trials have suggested that Radix astragali-based intervention can reduce symptoms, improve quality of life and immunologic function, increase plasma nerve growth factor levels, and delay the progression of CIPN (Deng et al. 2016). In a rat model of oxaliplatin-induced peripheral neuropathy, repeated administration with hydroalcoholic extract (50%HA) of Radix astragali fully prevented oxaliplatin-induced mechanical and thermal hypersensitivity and promoted the rescue mechanisms that protect nervous tissue from the damages triggering chronic pain (Di Cesare Mannelli et al. 2017). The hydroalcoholic extract of Radix astragali decreased the number of microglia and astrocyte in the spinal dorsal horn and brain and then resulted in pain relieving. In addition, the effect of Radix astragali in CIPN management is not due to the decrease of anticancer effect of chemotherapy (Deng et al. 2016). Furthermore, Radix astragali injection can enhance the antitumor effect of chemotherapy and it can improve the short-term prognosis and clinical outcome in children with acute lymphoblastic leukemia under chemotherapy (Wang et al. 2018).

3.2.2.2 Ginkgo Biloba

The leaves of Ginkgo biloba tree have been used in traditional Chinese medicine for several hundred years. Ginkgo biloba extract (GBE) comprised of 24% flavone glycosides and 6% terpene lactones; flavone glycosides are primarily made of quercetin, kaempferol, and isorhamnetin, whereas terpene lactones are made of ginkgolides A, B, and C and bilobalide (Park et al. 2012a). It is well known for its protective effects on nervous and circulatory systems. Several researches have reported its chemopreventive effect against cisplatin ototoxicity (Huang et al. 2007; Cakil et al. 2012; Dias et al. 2015; Mei et al. 2017). In a rat model of vincristine-induced peripheral neuropathy, the anti-hyperalgesic effects of oral GBE was observed. The paw withdrawal threshold to mechanical stimuli was significantly increased, and the withdrawal frequency to cold stimuli was significantly reduced in GBE-treated rat versus the control group dose-dependently (Park et al. 2012a). EGb761, a standardized extract of G. biloba leaves, is reported to alleviate symptoms or has neuroprotective effects in various central nervous system disorders. In a mice model of cisplatin-induced peripheral neuropathy, nerve conduction velocities were significantly slower in cisplatin-treated group than the cisplatin + EGb761-treated group. But the nerve conduction velocities were still scored faster in non cisplatin-treated group than cisplatin + EGb761-treated group. Studies from in vivo and in vitro indicated that EGb761 was effective in preventing some functional and morphological deterioration in cisplatin-induced peripheral neuropathy (Ozturk et al. 2004).

3.2.2.3 Acorus Calamus

Acorus calamus is used in the ancient system of medicine to ward off diseases. It has several phytochemical components such as glycosides, flavonoids, saponins, tannins, and polyphenols which show significant cholinesterase inhibitory properties. The plant is found to have potent antioxidant, anti-inflammatory, antimicrobial, wound-healing, radioprotective, pesticidal and insecticidal properties, immune-regulating, and neuroprotective activities (Khwairakpam et al. 2018). The attenuating potential of hydroalcoholic extract of Acorus calamus (HAE-AC) has been reported in a rat model of vincristine-induced neuropathic pain (Muthuraman et al. 2011). In this study, HAE-AC and pregabalin were administered for 14 consecutive days. The results showed that HAE-AC attenuated vincristine-induced thermal hyperalgesia and mechanical hyperalgesia and allodynia in a dose-dependent manner comparable to pregabalin. It was speculated that Acorus calamus prevented vincristine-induced neuropathic pain, which may be attributed to its multiple effects including antioxidative, anti-inflammatory, neuroprotective, calcium inhibitory actions, and so on (Muthuraman and Singh 2011).

3.2.2.4 Salvia

Salvia , also known as sage, is one of the most important genuses of Lamiaceae family with its culinary and medical use (Uritu et al. 2018). Its constituents can influence several biological targets including their effects on cholinergic activity, neurotrophins, oxidative stress, and inflammation (Lopresti 2017). It is one of the oldest medicinal plants used as a universal panacea by humans for its antibacterial, antiviral, antioxidative, anti-inflammatory, and antitumor effects. The pharmacological effects of Salvia essential oil are based on its more than 100 active compounds. Clinical trials showed that Salvia officinalis and Salvia lavandulaefolia exert beneficial effects by enhancing cognitive performance both in healthy subjects and patients with dementia or cognitive impairment, indicating its promising neuroprotective effects (Miroddi et al. 2014). Animal studies have demonstrated that vincristine causes painful effects, whereas Salvia officinalis shows analgesic and anti-inflammatory effects. Salvia officinalis hydroalcoholic extract significantly suppressed the vincristine- or cisplatin-enhanced pain in the second phase of formalin test (Abad et al. 2011b; Abad and Tavakkoli 2012).

3.2.2.5 Camellia sinensis (Green Tea)

Green tea has been consumed by the Chinese for centuries and is probably the most consumed beverage besides water. For green tea, fresh tea leaves from the plant Camellia sinensis are steamed and dried to inactivate the polyphenol oxidase enzyme. It is a famous herbal plant as an antioxidant with abundant health benefits (Saeed et al. 2017). There are several polyphenolic catechins in green tea, such as gallocatechin, epigallocatechin, epicatechin, and epigallocatechin-3-gallate (EGCG). (−) Epigallocatechin-3-gallate, the most active catechin, has been demonstrated to have important protective effects in neurodegenerative diseases (Zaveri 2006) and tumor invasion (Khan and Mukhtar 2010; Shirakami and Shimizu 2018). In a rat model of oxaliplatin-induced peripheral neuropathy, green tea extracts were orally administered once daily. The results showed that only oxaliplatin-treated rats displayed a lower thermal threshold than the rats treated with oxaliplatin and green tea extracts. But there was no significant difference between the two groups in sensory conduction velocities and the number of apoptotic-featured cells in TUNNEL staining. The results suggested that green tea extracts may be a useful adjuvant to alleviate oxaliplatin-induced sensory allodynia. However, it may not prevent morphometric or electrophysiological alterations induced by oxaliplatin (Lee et al. 2012).

3.2.2.6 Cinnamomi Cortex

Cinnamomi cortex (C. cortex) is a medicinal herb for treating common cold and influenza in traditional Chinese medicine. It is able to effectively attenuate influenza virus and inflammations. In a rat model of oxaliplatin-induced cold allodynia, water extract of Cinnamomi cortex was orally administered daily for 5 consecutive days, and the treatment of water extract dose-dependently alleviated oxaliplatin-induced cold allodynia in rats. The water extract treatment also suppressed the activation of astrocytes and microglia and the expression levels of IL-1β and TNF in the spinal cord induced by oxaliplatin. It indicated that C. cortex has a potent anti-allodynic effect in oxaliplatin-injected rats through inhibiting spinal glial cells and pro-inflammatory cytokines (Kim et al. 2016).

3.2.2.7 Matricaria Chamomilla

Matricaria chamomilla (MC), also known as chamomile, is used to brew from dried flowers for sedation, pain management, anti-inflammation, and antioxidation and wound healing in traditional medicine. Chamomile has moderate antioxidant and antimicrobial activities, while animal studies indicate its potent anti-inflammatory action (McKay and Blumberg 2006). The analgesic and anti-inflammatory effects have been proved in humans for painful mouth ulcers and pain during parturition. By using formalin test in mice, MC hydroalcoholic extract not only decreased pain responses to formalin in the first and second phase, it also decreased the second phase of cisplatin-induced pain significantly (Abad et al. 2011a).

In addition, many other single herbs, such as Xylopia aethiopica, Synedrella nodiflora, Plantaginis semen, Achyranthis radix, Lithospermi radix, Aconiti tuber (Buja), Ocimum sanctum, Agrimonia eupatoria, etc. have been demonstrated to be effective in CIPN management in preclinical studies (Table 4).

Table 4 Preclinical studies of single herbs in the management of chemotherapy-induced peripheral neuropathy

3.2.3 Active Compounds

In this section, we will choose some active ingredients from herbs which had been confirmed to be effective in CIPN management and give a brief introduction regarding clinical and preclinical studies.

3.2.3.1 Curcumin

Curcumin , the main phenolic compound of the spice turmeric (Rhizoma curcumae) and part of the mixture of compounds referred to as curcuminoids (Nelson et al. 2017; Ammon and Wahi 1991), is a kind of natural product (NPs) exhibiting anti-inflammatory (Panahi et al. 2015) and antioxidant activity (Sahebkar 2015), especially in curcumin glucuronides – the major curcumin metabolites (Choudhury et al. 2015). The anti-inflammatory and antioxidant properties of curcumin may be attributed to its antinociceptive activity against different pain conditions, including peripheral neuropathic, inflammatory, postoperative, and burn pain, as well as its use as an oral supplement in the treatment of various inflammatory conditions. In a randomized control trial (Belcaro et al. 2014), patients treated with lecithinized curcumin (Meriva: 500 mg) for 60 days from 1st cycle of cancer chemotherapy showed significantly reduced chemotherapy-induced side effects when compared to the placebo-treated patients. Furthermore, the plasma levels of free radicals were obviously lower in the patients treated with lecithinized curcumin than the placebo-treated patients.

It has been reported that curcumin could improve platinum-based drug cisplatin- or oxaliplatin-induced thermal hypoalgesia and mechanical allodynia in rat models (Zhang et al. 2020b; Agthong et al. 2015). Electrophysiological test showed that curcumin could increase both motor and sensory nerve conduction velocity, indicating its favorable effects on functional deficits caused by the platinum drugs (Zhang et al. 2020b). The protective effect of curcumin against CIPN was further confirmed by the increasing level of sciatic functional index in male Swiss albino mice of alkaloid vincristine-induced sciatic functional loss and by the improvement in histopathology of the sciatic nerve, blockade of nuclear, nucleolar atrophy, and neuronal loss in platinum-induced neurotoxicity (Babu et al. 2015). Furthermore, curcumin exerted its antinociceptive activity against CIPN by decreasing oxidative stress markers, increasing the endogenous antioxidative enzymes, and suppressing inflammatory proteins and cytokines (Zhang et al. 2020b). The pretreatment with curcumin reduced the incidence of micronuclei and DNA damage induced by cisplatin and methotrexate (Said Salem et al. 2017). For now, curcumin nanoparticles form can be formulated to avoid the limited curcumin absorbed in the systemic circulation, and it is clear that curcumin nanoparticles could ameliorate the neurotoxic effect induced by cisplatin (Khadrawy et al. 2018). In addition, curcumin has been shown to possess antitumor properties (Thangapazham et al. 2006) and hence has been described as a well-tolerated chemotherapy adjunct (James et al. 2015; Zangui et al. 2019; Wei et al. 2017).

3.2.3.2 Cannabinoids

Cannabis sativa has been used to treat neuropathic pain since ancient time. In a retrospective analysis of 513 patients treated with oxaliplatin and 5-fluorouracil-based combinations (Waissengrin et al. 2021), the rate of neuropathy was lower among patients treated with cannabis and oxaliplatin, and this reduction was more significant in patients who received cannabis prior to treatment with oxaliplatin. The study suggested a protective effect of cannabis in CIPN management. As the components of the Cannabis sativa (marijuana) plant, cannabinoids have been demonstrated to suppress neuropathic nociception in animal models through CB1 and CB2 receptor-specific mechanisms located in the central nervous system and immune cells (Pacher et al. 2006; Sagar et al. 2005; Mechoulam et al. 2002). Moreover, cannabinoids play an important role in preventing several other adverse side effects of chemotherapy including organ toxicity, pain, and loss of appetite (Mortimer et al. 2018). The delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are two important forms of cannabinoids. A multicenter, double-blind, randomized, placebo-controlled study shows that THC:CBD extract is efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids (Johnson et al. 2010). Another case study confirms the potential effect of CBD to improve chemoradiation responses that impact survival (Dall’Stella et al. 2018). The effect of CBD and THC in CIPN management has also been demonstrated in the animal model of chemotherapy-induced peripheral neuropathy (Alkislar et al. 2021; Foss et al. 2021).

As a major nonpsychotropic constituent of cannabis, CBD is devoid of psychoactive properties because of a low affinity for the CB1 and CB2 receptors (Pacher et al. 2006), constituting up to 40% of Cannabis sativa plant extract (Campos et al. 2012). Systemic administration of the CB1/CB2 receptor agonist suppressed vincristine- or paclitaxel-evoked neuropathic pain while CB2 receptors may be the important therapeutic target (Rahn et al. 2007; Rahn et al. 2008). Preliminary projects found cannabidiol may prevent the development of paclitaxel-induced allodynia in mice and is protective against neurotoxicity mediated in part by the 5-HT_1A receptor system (Ward et al. 2014; Ward et al. 2011). Meanwhile, another data demonstrated that each of the major constituents of Sativex (a 1:1 ratio of tetrahydrocannabinol and cannabidiol) alone can achieve analgesic effects against cisplatin neuropathy (Harris et al. 2016). But in a mouse model of chemotherapy-induced peripheral neuropathy, both CBD and THC showed effective in attenuating mechanical allodynia in mice with paclitaxel, while CBD attenuated oxaliplatin but not vincristine-induced CIPN and THC attenuated vincristine but not oxaliplatin-induced CIPN (King et al. 2017).

3.2.3.3 Tetrahydropalmatine

Corydalis yanhusuo is a perennial herb in the Papaveraceae family as an old traditional Chinese medicine which demonstrated analgesic efficacy in humans. There is a widely used Chinese herbal pain-relieving formulation called the “Yuanhu analgesic capsule” consisting Corydalis yanhusuo. Yuan et al. demonstrated that after a single, oral administration of the extracts of Corydalis yanhusuo and Angelicae dahuricae, the pain intensity and pain bothersomeness scores significantly decreased in humans (Yuan et al. 2004). Levo-tetrahydropalmatine (L-THP) has been identified as one of the major active components of Corydalis yanhusuo and it has been used clinically in China for more than 40 years as an analgesic with sedative/ hypnotic properties. Preclinical studies suggested the possible clinical utility of L-THP in the treatment of bone cancer pain, and it may inhibit microglial cells activation and the increase of proinflammatory cytokines (Zhang et al. 2015). It also alleviated mechanical hyperalgesia in models of chronic inflammatory and neuropathic pain in mice (Zhou et al. 2016a). In a mouse model of CIPN, the L-THP was reported to produce a dose-dependent anti-hyperalgesic effect on chemotherapeutic agent oxaliplatin-induced neuropathic pain via a dopamine D1 receptor mechanism (Guo et al. 2014). In an in vitro study, a cisplatin-resistant human ovarian cancer cell line was incubated with L-THP with cisplatin, and the results showed that L-THP increased the sensitivity of ovarian cancer cells to cisplatin via modulating miR-93/PTEN/AKT pathway (Gong et al. 2019). In spite of these, more studies are still needed for evaluation of the L-THP for clinical CIPN prevention.

3.2.3.4 Auraptenol

Auraptenol is a phytochemical isolated from Angelicae dahuricae radix (Baizhi) (Lee and Kim 2016; Wu et al. 2019a). The roots of the plant are used to alleviate pain in humans as an old traditional Chinese medicine. Previous studies showed that its antinociceptive effects may contribute to the release of endogenous opioids. In clinical trials, a single oral administration of A. dahuricae decreased cold-induced tonic pain in a dose-dependent manner (Lee and Kim 2016). In a mouse model of vincristine-induced mechanical hyperalgesia, auraptenol dose-dependently (0.05–0.8 mg/kg) reversed the vincristine-induced mechanical hyperalgesia, and the anti-hyperalgesic effect was blocked by a selective serotonin 5-HT_1A receptor antagonist (Wang et al. 2013). All these suggested that auraptenol might be a potential candidate for CIPN prevention.

3.2.3.5 Flavonol (Rutin and Quercetin)

The flavonoids rutin (also known as vitamin P) and quercetin are polyphenolic compounds found in vegetables, fruits, and seeds. Flavonoids are reported for their activity against cancer progression, especially antioxidant activities or scavenging properties (Schwingel et al. 2014). Several studies have showed that these flavonoids have protective effect of nephrotoxicity (Alhoshani et al. 2017), DNA damage (Jahan et al. 2018), oxidative cardiovascular damage (Topal et al. 2018), hepatotoxicity, and neurotoxicity (Schwingel et al. 2014; Almutairi et al. 2017) induced by chemotherapy. It has been reported that the co-delivery of vincristine- and quercetin-loaded lipid-polymeric nanocarriers exhibited the best antitumor efficacy (Zhu et al. 2017). In a mice model of oxaliplatin-induced CIPN, rutin and quercetin (25–100 mg/kg, intraperitoneal) were injected 30 min before each oxaliplatin injection, and the results indicated that rutin and quercetin prevented oxaliplatin-increased thermal and mechanical nociceptive response (Azevedo et al. 2013). Further investigation showed that the inhibition effect of the rutin and quercetin on oxaliplatin-induced chronic pain was probably due to the reduction of nitric oxide and peroxynitrite in the spinal cord (Azevedo et al. 2013). Furthermore, rutin has been found to prevent cisplatin-induced oxidative retinal and optic nerve injury, as well as lipid peroxidation, oxidative stress, inflammation markers, and histopathological damage (Tasli et al. 2018). The preventive effect of quercetin on CIPN was also confirmed in paclitaxel-induced peripheral neuropathy in rats and mice (Gao et al. 2016). All these suggested that rutin may show the potential activity on chemotherapy-induced peripheral neuropathy.

3.2.3.6 Borneol

(+)-Borneol , a bicyclic monoterpene obtained by distillation and recrystallization from the leaves of Blumea balsamifera DC or the stem leaves of Cinnamomum camphora, is used for analgesia and anesthesia in traditional Chinese medicine. It has been known that TRPM8 channel was a molecular target of borneol. Previous findings suggest that (+)-borneol may ameliorate mechanical hyperalgesia by enhancing GABA_AR-mediated GABAergic transmission in the spinal cord and could serve as a therapeutic for chronic pain (Jiang et al. 2015). A randomized, double-blind, placebo-controlled clinical study examined the analgesic efficacy of topical borneol involving 122 patients with postoperative pain (Wang et al. 2017). The results indicated that topical application of borneol led to significantly greater pain relief than placebo did. It showed that topical borneol-induced analgesia was almost exclusively mediated by TRPM8. In a mice model of oxaliplatin-induced neuropathic pain, (+)-borneol treatment significantly reverses oxaliplatin-induced mechanical hyperalgesia in a dose-dependent manner. However, (+)-borneol treatment did not alter the body weight and locomotor activity, and repeated treatment with (+)-borneol did not induce the development of antinociceptive tolerance. It was known that the analgesic efficacy of (+)-borneol was conducted by blocking transient receptor potential ankyrin 1 in the spinal cord (Zhou et al. 2016b). Now, borneol is currently approved by US FDA to be used only as a flavoring substance or adjuvant in food (21 CFR 172.515). More evaluations of the antinociceptive effect by borneol are still needed.

In addition, there are many active ingredients which show a promising effect in preventing and treating CIPN in preclinical studies (Table 5).

Table 5 Preclinical studies of active components from herbs in the management of chemotherapy-induced peripheral neuropathy

3.3 Exercise (Kinesiatrics)

Many studies have demonstrated that exercise has positive effects in improving CIPN symptoms of cancer patients. Exercise has been found to reduce CIPN symptoms through sensory pathways; induce an anti-inflammatory environment; increase the supply of blood, glucose, and oxygen to mitochondria; and improve sensorimotor functions of cancer patients undergoing CIPN. The exercise intervention increased the muscle strength, balance, and postural stability of cancer patients (Lin et al. 2021). A meta-analysis includes five studies from Germany, the USA, India, and Canada which evaluated the effects of exercise on chemotherapy-induced peripheral neuropathy symptoms in cancer patients (Lin et al. 2021). Totally, 178 cancer patients successfully completed the exercise program, which includes muscle strengthening and balancing exercises, sensorimotor-based exercises, and nerve gliding exercises. The frequency and duration vary from twice a week for 4 weeks to thrice a week for 18 weeks to seven times per week for 10 weeks. The meta-analysis results indicated that the exercise intervention did significantly improve the mean CIPN scores of the cancer patients. Table 6 lists several clinical studies about exercise on chemotherapy-induced peripheral neuropathy.

Table 6 Clinical trials of exercise application in CIPN management

Yoga is a popular meditative movement therapy that improves body conditioning, flexibility, and balance. It combines postures, breathing exercises, and meditation to cultivate connection between mind and body. Bao et al. reported the promising efficacy of yoga in improving CIPN symptoms (Bao et al. 2020). In this study, the yoga group practiced 60 min of yoga daily for 8 weeks, and it included in-person group classes twice a week and at-home practice five times per week. Similar to other exercises, modifiable posture training is considered to increase musculoskeletal flexibility, strength, and balance, while breathing exercise is to engage relaxation response and meditation is to decrease stress/anxiety associated with pain. Therefore, yoga may result in modulation of the neuroendocrine system through the hypothalamic-pituitary-adrenal axis. So, yoga is often used by cancer survivors for symptom management, with effects on physical and mental health.

Animal studies also showed that exercise is beneficial for the management of CIPN. In a mice model of paclitaxel-induced peripheral neuropathy, running exercises during the onset of CIPN could delay the onset of paclitaxel-induced peripheral neuropathy, but it cannot prevent the development of paclitaxel-induced peripheral neuropathy. And running exercises during maintenance of CIPN could reduce already established mechanical and cold allodynia induced by paclitaxel. Furthermore, running exercises can partially abrogate paclitaxel-induced axonal degeneration, including reduction in epidermal nerve fibers density in the plantar of hind paw and thermal hypoalgesia.

3.4 Cryotherapy

Cryotherapy , also named cold application or therapeutic regional hypothermia, a nonpharmacological method by applying cooling to distal extremities, showed an important role in the management of CIPN symptom (Sphar et al. 2020). It could induce vasoconstriction due to the local effect of the cold, decrease blood flow, and hence slow the cellular metabolism and reduce the peripheral exposure to anticancer drugs (Simsek and Demir 2021; Sato et al. 2016). It could also reduce the sensitivity of nociceptors by reducing the release of vasodilator substances (Simsek and Demir 2021). By covering the hands and feet of patients with cold insulator, frozen gloves and socks, or cold packs around wrists and ankles, the cryotherapy has been reported to reduce the severity of chemotherapy-induced neuropathy in several studies (Sato et al. 2016; Scotte et al. 2005; Sphar et al. 2020). In a multicenter study, a frozen glove was used by 45 cancer patients during every docetaxel infusion (Scotte et al. 2005). Each cryotherapy included a total of 90 min cryotherapy (15 min before docetaxel infusion, during the 1-h docetaxel infusion, and 15 min after the end of infusion). The results showed that cryotherapy significantly reduced the nail and skin toxicity associated with docetaxel. In addition, Hanai et al. reported that the incidence of objective and subjective signs of CIPN, such as warm sense and tactile sensitivity of hand and foot, was significant lower in the patients who used frozen gloves and sock than in the patients who did not use (Hanai et al. 2018). Sato et al. also reported that the incidence rate of ≥ grade 2 peripheral neuropathy in cryotherapy was significantly lower than that observed in the patients without cryotherapy (Sato et al. 2016). All these suggest that cryotherapy might be an effective way to manage CIPN. It should be noted that cold-induced pain as adverse event has been reported (Sato et al. 2016).

3.5 Massage

Massage is one of the most commonly used manual therapies for holistic treatment of patients. It has been widely recommended by professionals for prevention and palliation of cancer-related symptoms, including CIPN (Niemand et al. 2020; Izgu et al. 2019a). Massage is considered to reduce CIPN symptoms and improve the patients’ quality of life by increasing circulation. In an assessor-blinded randomized controlled trial of a total of 40 female breast cancer patients, the peripheral neuropathic pain was lower in patients receiving classical massage (Swedish massage) compared to the patients without massage (Izgu et al. 2019a). The results indicate that classical massage successfully prevented chemotherapy-induced neuropathic pain, improved the quality of life, and showed benefits to nerve conduction study findings. In addition, aromatherapy massage and foot massage also show the beneficial effects on CIPN symptoms (Park and Park 2015; Izgu et al. 2019b; Noh and Park 2019).

3.6 Other Complementary Therapies

Photobiomodulation therapy or low-level laser therapy is a light therapy from light-emitting diodes and/or laser diodes (Lodewijckx et al. 2020). It is used to stimulate tissue repair and reduce inflammation and neuropathic pain. It has become a new treatment modality with supportive cancer care. In a randomized sham-controlled clinical trial, Argenta et al. reported that 30-min sessions of photobiomodulation three times weekly for 6 weeks significantly reduced neuropathy score of cancer patients at all observing time points, while sham treatment showed no significant effect on neuropathy score at all observing time points (Argenta et al. 2017). The results indicate that photobiomodulation has a beneficial effect in improving chemotherapy-induced peripheral neuropathy.

In addition, music therapy and foot bathing are often used as adjuvants to other therapies, such as acupuncture, reflexology, acupressure, and mind-body therapies. However, current evidence of these therapies is very limited. More randomized, controlled, multicenter, and methodologically uniform research is needed to support the use of these therapies for the management of CIPN (Lodewijckx et al. 2020).

4 Potential Mechanisms

Accumulating evidence indicates that the initiation and progression of CIPN are tightly related with the loss of IENFs, abnormal spontaneous discharge, degeneration of DRG, oxidative stress, ion channel activation, and neuro-immune system activation (Hu et al. 2019; Hu et al. 2018; Zhang et al. 2016; Sisignano et al. 2014). Alternative medicine has been found to treat CIPN through neuroprotective pathway and antioxidative stress, reduce inflammation, regulate ion channel activation, and regulate endogenous pain modulation system.

4.1 Acupuncture Therapy

Our previous study showed that repeated cisplatin exposure increased the proinflammatory cytokines, such as IL-1β, TNF-α, and IL-6, as well as proinflammatory microglial marker-inducible nitric oxide synthase (iNOS) and CD16, in the spinal dorsal horn of mice. Intraperitoneal (i.p.) or intrathecal (i.t.) injection with minocycline, an inhibitor of microglia, both alleviated cisplatin-induced mechanical allodynia, sensory deficits, and IENFs loss. Further investigation indicated that the spinal microglial activation induced by cisplatin was mediated by cisplatin-enhanced triggering receptor expressed on myeloid cells 2 (TREM2)/DNAX-activating protein of 12 kDa (DAP12) signaling. I.t. administration of an anti-TREM2-neutralizing antibody prominently prevented cisplatin-induced mechanical allodynia, sensory deficit, and IENFs loss and suppressed the spinal IL-6, TNF-α, iNOS, and CD16. Our results demonstrated that cisplatin triggered persistent microglial activation in the spinal cord through strengthening TREM2/DAP12 signaling, which resulted in CIPN (Hu et al. 2018). Pretreatment with EA (EA was applied 1 day before the first cisplatin injection) significantly suppressed cisplatin-induced microglial activation, inflammatory response, and upregulation of TREM2 and DAP12. The preventive effect of EA on cisplatin-induced CIPN was blocked by downregulating neuronal G protein-coupled receptor kinase 2 (GRK2), which has been demonstrated to play a role in regulating inflammatory pain, in the spinal cord. The upregulation of neuronal GRK2 in the spinal cord significantly prevented the cisplatin-induced CIPN, suppressed the microglial activation, as well as increased TREM2 and DAP12 in the spinal cord. Our results suggested that neuronal GRK2-mediated TREM2 and DAP12 inhibition, resulted in neuroinflammation resolving in the spinal cord contributed to the preventive effect of EA on CIPN. In addition, in a rat model of paclitaxel-induced peripheral neuropathy, EA treatment significantly inhibited the paclitaxel-evoked astrocyte and microglial activation in the spinal cord (Li et al. 2019b).

Xainze Meng et al. reported that in a rat model of paclitaxel-induced peripheral neuropathy, EA at 10 Hz significantly decreased response frequency to von Frey filaments (4–15 g) compared to sham EA (Meng et al. 2011). Either μ, κ, or δ opioid receptor antagonist inhibited EA inhibition of mechanical allodynia and hyperalgesia. The results suggested that EA inhibited paclitaxel-induced allodynia/hyperalgesia through spinal opioid receptors. In a mouse model of paclitaxel-induced peripheral neuropathy (Choi et al. 2015), the antinociceptive effect and the suppression of EA stimulation on paclitaxel-enhanced phosphorylation of NMDA receptor NR2B subunit were reduced by intrathecal pretreatment with naloxone (opioid receptor antagonist), idazoxan (alpha2-adrenoceptor antagonist), or propranolol (beta-adrenoceptor antagonist). The results suggested that EA alleviated CIPN via the mediation of opioid receptor, alpha2- and beta-adrenoceptors in the spinal cord.

Transient receptor potential vanilloid 1 (TRPV1) channel is a nonselective cation channel mainly expressed in nociceptive primary sensory neurons. Toll-like receptor 4 (TLR4) plays an important role in chronic pain, which are colocated with TRPV1 in DRG neurons (Li et al. 2015). In a rat model of paclitaxel-induced peripheral neuropathy, TRPV1 and TLR4 expression are upregulated in DRG neurons, whereas TRPV1 antagonists or TLR4 antagonist significantly reduced paclitaxel-induced pain, suggesting that TRPV1 contributes to paclitaxel-induced CIPN (Li et al. 2014, 2015). Paclitaxel is supposed to activate TLR4 and its downstream signaling to promote the activity of TRPV1 channel in DRG, resulting in sustained peripheral neuropathy. EA treatment significantly suppressed paclitaxel-evoked overexpression of TRPV1, TLR4, and its downstream signaling myeloid differentiation primary response 88 (MyD88) (Li et al. 2019b). The results suggested that EA alleviates paclitaxel-induced peripheral neuropathy possibly by suppressing TLR4 signaling and TRPV1 activation in DRG neurons.

Intraepidermal nerve fibers (IENFs) are free nerve ending arising from unmyelinated and thinly myelinated sensory neurons within the dermis and are important for sensation and pain transmission (Boyette-Davis et al. 2011a). Both in human or animals treated with chemotherapy, the density of IENFs in distal limbs is significantly reduced (Pachman et al. 2011; Mao-Ying et al. 2014; Hu et al. 2018). Our previous results showed that preventive EA treatments significantly prevent the IENFs loss induced by cisplatin. Furthermore, the cisplatin-induced IENFs loss could be prevented by intrathecal injection of minocycline or an anti-TREM2 neutralizing antibody (Hu et al. 2018). However, our study also showed that repeated exposure to cisplatin of mice displayed loss of epidermal Merkel cells, which are critical for tactile sensation, in the hind paw (Hu et al. 2018). The preventive treatment with EA significantly inhibited the cisplatin-induced Merkel cell loss in mice. It is interesting that the loss of Merkel cell was not dependent on microglial activation in the spinal cord (Hu et al. 2018). I.p. or i.t. administration of minocycline had no effect on Merkel cell loss of hind paw induced by cisplatin treatment. It may suggest that there are other mechanisms involved in the EA effect on CIPN management.

4.2 Herbal Medicine

Herbal medicine possesses the characteristic of multiple active compounds, multiple targets, and multiple pathway formula. The active compounds and targets consist of a complicated network. For example, 63 active compounds were retrieved from Huangqi Guizhi Wuwu Tang, with an herb-composite compound-target network including 748 nodes and 5448 edges. The network analysis and literature reviews show that Huangqi Guizhi Wuwu Tang may play a therapeutic role in regulating inflammatory response and repairing nerve injury, which may be the two main pathological processes of CIPN (Gu et al. 2020). In this section, we will summarize the potential mechanism attribute to the effect of herbal medicine on CIPN.

4.2.1 Neuroprotective Effect

The myelinated peripheral sensory fibers , including Aδ- and Aβ-fibers, are responsible for sensing fast pain and tactile pressure, respectively. It has been reported that oxaliplatin causes a significant increase in the responsiveness of myelinated peripheral sensory neurons, while Niuche Shenqi Wan significantly inhibited the sensitization of Aδ- and Aβ-fibers (Mizuno et al. 2016). Though Aβ-fibers sense innocuous tactile stimuli in physiological conditions, they transmit tactile stimuli as pain in pathological conditions. It is most likely that the sensitization of either Aδ- or Aβ-fibers or both is involved in the development of oxaliplatin-induced mechanical allodynia and that Niuche Shenqi Wan alleviates oxaliplatin-induced mechanical allodynia via acting on the Aδ- or Aβ-fibers and inhibiting their sensitization. In addition, a morphological analysis showed that the atrophy of axons containing myelinated nerve fibers but not nonmyelinated nerve fibers was observed in the sciatic nerves of oxaliplatin rats and Niuche Shenqi Wan ameliorated it (Kono et al. 2015).

In a rat model of paclitaxel-induced peripheral neuropathy (Matsumura et al. 2014), electron microscope findings showed that clear degeneration of the nucleus and swelling of the mitochondria in dorsal root ganglion cells were observed in paclitaxel-treated rats, indicating that paclitaxel induced neurodegenerative alteration. But there was no obvious degeneration of the nucleus and swelling of the mitochondria in rats treated with paclitaxel and Niuche Shenqi Wan (or goshajinkigan). The results suggested that Niuche Shenqi Wan might prevent paclitaxel-induced degeneration of the ganglion cells.

Furthermore, it has been demonstrated that oxaliplatin treatment suppressed neurite outgrowths from primary DRG cells in vitro, whereas Nin-jin’yoeito extract dose-dependently blocked this suppression (Suzuki et al. 2017). Further investigation showed that among the herbal components of Nin-jin’yoeito, the extract of ginseng showed a protective effect against oxaliplatin-induced neurite damage. An ex vivo study showed that 50% hydroalcoholic extracts of Astragali radix significantly reduced morphometric and molecular alterations induced by oxaliplatin in peripheral nerve and dorsal root ganglia, but it did not alter oxaliplatin-induced apoptosis of colon tumors in an Apc-driven rat model of colon carcinogenesis (Di Cesare Mannelli et al. 2017). Similarly, aqueous extracts of F. suspensa fruits or Forsythia viridissima fruits remarkably attenuated oxaliplatin-induced neurotoxicity in vitro (Yi et al. 2019a, b).

In a mice model of paclitaxel-induced peripheral neuropathy, the mice displayed enhanced lipid peroxidation in peripheral nerve due to paclitaxel treatment which was reflected as a significant increase of malondialdehyde (MDA), oxidized glutathione (GSSG), and glutathione (GSH):GSSG compared to normal mice (Balkrishna et al. 2020). Herbal decoction Divya-Peedantak-Kwath treatment significantly decreased the MDA, GSSG, and GSH:GSSG level due to paclitaxel treatment. In addition, paclitaxel treatment induces axonal degeneration and swelling and lymphocytic infiltration of sciatic nerve, and Divya-Peedantak-Kwath treatment restored the redox potential of the sciatic nerves to normal. This indicates that Divya-Peedantak-Kwath treatment alleviates the oxidative stress and nerve damage imposed by paclitaxel treatment.

In a mouse model of paclitaxel-induced peripheral neuropathy, repetitive application of paeoniflorin , one principal bioactive constituent of Paeoniae radix, significantly attenuated paclitaxel-induced allodynia, suppressed saphenous nerve firing, and demyelination in the plantar nerve evoked by paclitaxel (Andoh et al. 2017a). In addition, Siwei Jianbu Tang, aqueous extract of F. suspensa fruits, Lithospermi radix, and Corydalis saxicola Bunting total alkaloids could prevent oxaliplatin-induced IENF loss in footpads of mice (Zhang et al. 2020a; Yi et al. 2019a; Cho et al. 2016; Kuai et al. 2020).

The neuroprotective effects were also observed on Vernonia cinerea, Ginkgo biloba (EGb761), Butea monosperma, and curcumin in the peripheral nerve system (Thiagarajan et al. 2014; Ozturk et al. 2004; Thiagarajan et al. 2013; Agthong et al. 2015) and on curcumin in spinal dorsal horn (Zhang et al. 2020b).

4.2.2 Anti-inflammation

Accumulating evidence indicated that the central glia play an important role in CIPN (Hu et al. 2018; Ji et al. 2013). In a rat model of vincristine-induced peripheral neuropathy (Ji et al. 2013), vincristine evoked obvious astrocyte rather than microglia activation. The vincristine-induced mechanical allodynia was dose-dependently attenuated by i.t. administration of L-α-aminoadipate (LAA, an astrocytic specific inhibitor) but not by minocycline (a microglial inhibitor). The results indicated that the astrocyte activation in the spinal cord contributes to vincristine-induced CIPN. In a mouse model of oxaliplatin-induced peripheral neuropathy, oxaliplatin causes an increase of reactivated astrocyte but not microglia, and the reactivated astrocyte was inhibited by repetitive administration of Kei-kyoh-zoh-soh-oh-shin-bu-toh (Korean) (Andoh et al. 2019). But in a mouse model of cisplatin-induced peripheral neuropathy, the microglial rather than astrocyte activation has been demonstrated to contribute to the development of CIPN (Hu et al. 2018).

In a rat model of oxaliplatin-induced peripheral neuropathy, daily oral administration of Gyejigachulbu-tang markedly attenuated oxaliplatin-induced cold and mechanical hypersensitivity and markedly inhibited oxaliplatin-induced increase of glial fibrillary acidic protein (GFAP, astrocyte marker) and OX-42 (microglia marker) in the spinal cord, indicating that Gyejigachulbu-tang may relieve oxaliplatin-induced CIPN by suppressing spinal glial activation (Ahn et al. 2014). Another study in a rat model of oxaliplatin-induced neuropathy showed that 50% of hydroalcoholic extracts of Astragali radix significantly decreased the oxaliplatin-evoked activation of astrocyte and microglia in the spinal cord and brain areas (Di Cesare Mannelli et al. 2017). Similarly, the inhibitory effects on the activation of astrocyte and microglia and the upregulation of IL-1β and TNF in the spinal cord due to oxaliplatin were also observed on Cinnamomi cortex, Buja, Lithospermi radix, and coumarin (a major phytocompound of Cinnamomi cortex) (Kim et al. 2016; Jung et al. 2017; Cho et al. 2016). But in a rat model of paclitaxel-induced peripheral neuropathy, though paclitaxel induced both astrocyte and microglia activation, cinobufacini (a water extract of the dried toad skin) only suppressed astrocyte activation and decreased production of spinal TNF-α and IL-1β in the spinal cord (Ba et al. 2018). The suppression on spinal neuroinflammation was also observed on curcumin and matrine (a major component of Sophora alopecuroides L.) in animal chemotherapy (Gong et al. 2016; Zhang et al. 2020b).

In the DRG, TNF-α, IL-6, and IL-1β mRNAs were upregulated in oxaliplatin-treated mice, and prophylactic administration of Siwei Jianbu Tang effectively inhibited these upregulations (Zhang et al. 2020a). Further investigation showed that Siwei Jianbu Tang prevented oxaliplatin-induced peripheral neuropathy by activating p38, ERK1/2, and NF-κB signaling without activating p-JNK/JNK. In a mouse model of paclitaxel-induced peripheral neuropathy, paclitaxel increased the level of NF-κB, p-ERK1/2, p-JNK, as well as TNF-α, IL-6, and IL-1β, and Siwei Jianbu Tang inhibited the increase of NF-κB, p-ERK1/2, and p-JNK and restrained the paclitaxel-evoked inflammatory cytokines in DRG of mice (Suo et al. 2020).

In addition, in a rat model of vincristine-induced peripheral neuropathy, vincristine administration induced a significant rise in TNF-α level in the sciatic nerve endings (Muthuraman et al. 2011). Pretreatment with hydroalcoholic extract of Acorus calamus attenuated the vincristine-evoked increase of TNF-α level, and the effect was similar with pregabalin treatment. The results indicated that Acorus calamus prevented vincristine-induced neuropathic pain, which may be attributed to its anti-inflammatory activity. Another study showed that the inflammatory mediators (TNF-α, IL-1β, and IL-6) in sciatic nerve were attenuated by saponins from Tribulus terrestris in a rat model of vincristine-induced peripheral neuropathy, indicating the anti-inflammatory activity of saponins (Gautam and Ramanathan 2019).

As compared to the normal control mice, mice treated with paclitaxel showed a significant increase of mean serum TNF-α level, and herbal decoction Divya-Peedantak-Kwath treatment significantly decreased the mean serum TNF-α level (Balkrishna et al. 2020). This indicates that Divya-Peedantak-Kwath treatment alleviates the concomitant inflammation imposed by paclitaxel treatment. In another study of mice treated with oxaliplatin, the inflammatory-related factors were significantly increased in mouse serum after oxaliplatin injection, and prophylactic administration of Siwei Jianbu Tang effectively improved this phenomenon (Zhang et al. 2020a). Similarly, Corydalis saxicola Bunting total alkaloid administration could also normalize cisplatin-evoked upregulation of TNF-α, IL-1ß, and PGE2 in serum and paw of rats (Kuai et al. 2020).

All these indicate that the herbal medicine might protect against CIPN via inhibiting the chemotherapeutic drug-evoked inflammatory responses in the central and peripheral nervous system as well as peripheral tissues.

4.2.3 Antioxidative Stress

Chemotherapeutic drugs cause oxidative stress , which resulted in nerve degeneration. Studies had been demonstrated that the herbal medicine may prevent CIPN by their antioxidative activity (Muthuraman and Singh 2011). In a rat model of vincristine-induced peripheral neuropathy, vincristine administration induced a significant rise in superoxide anion generation level and myeloperoxidase activity in the sciatic nerve endings (Muthuraman and Singh 2011; Muthuraman et al. 2011). Pretreatment with hydroalcoholic extract of Acorus calamus attenuated the vincristine-evoked increase of these biomarkers; the effect was similar with pregabalin treatment. The results indicated that Acorus calamus prevented vincristine-induced neuropathic pain, which may be attributed to its antioxidative activity.

In addition, in a rat model of oxaliplatin-induced peripheral neuropathy, oxaliplatin reduced antioxidant levels, such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT), but oxaliplatin increased peroxidation levels and malondialdehyde (MDA) in the spinal cord (Zhang et al. 2020b). Curcumin increased antioxidant enzymes and reduced peroxidation to maintain the balance of redox. The study implies that curcumin may alleviate oxaliplatin-induced peripheral neuropathy by inhibiting oxidative stress-mediated activation of NF-κB and mitigating neuroinflammation (Zhang et al. 2020b). Curcumin has also been demonstrated to exert its antioxidant effect in the sciatic nerve of vincristine-treated mice (Babu et al. 2015).

The potential ameliorative effect on oxidative stress induced by chemotherapeutic drugs was also observed on Ocimum sanctum, Vernonia cinerea, Butea monosperma (Kaur et al. 2010; Thiagarajan et al. 2013, 2014), and matrine (a major component of Sophora alopecuroides L.), rutin, and quercetin (Gong et al. 2016; Azevedo et al. 2013).

4.2.4 Ion Channel Regulation

Cumulated evidence indicates that the transient receptor potential (TRP) family plays a critical role in the pathology of painful CIPN (Hu et al. 2019). It has been reported that an upregulation of the transient receptor potential melastatin 8 (TRPM8) and transient receptor potential ankyrin 1 (TRPA1) channels, which are cold-gated ion channels, is responsible for the cold-evoked pain response after chemotherapeutic exposure. In a rat model of oxaliplatin-induced peripheral neuropathy (Kato et al. 2014), coadministration of Niuche Shenqi Wan (or goshajinkigan) and oxaliplatin significantly reduced the withdrawal response to cold stimulation and the expression level of TRPM8 and TRPA1 mRNA in the L4-L6 DRG when compared with rats treated with oxaliplatin alone. The result suggests that Niuche Shenqi Wan (or goshajinkigan) may improve oxaliplatin-induced cold pain by suppressing TRPM8 and TRPA1 expression in DRG. Similar result was found in Shaoyao Gancao Tang (Shakuyakukanzoto), and repetitive administration of Shaoyao Gancao Tang inhibited the oxaliplatin-evoked TRMP8 mRNA expression in the DRG (Andoh et al. 2017b). In a mouse model of oxaliplatin-induced peripheral neuropathy, (+)-borneol, a bicyclic monoterpene present in the essential oil of plants, was considered to exert remarkable antinociceptive effect by blocking TRPA1 in the spinal cord (Zhou et al. 2016b). TRPA1 inhibition has also been demonstrated to attribute to the antinociceptive effect of Tabernaemontana catharinensis ethyl acetate fraction (Brum et al. 2019).

Transient receptor potential vanilloid 4 (TRPV4) has been reported to be responsible for the mechanical allodynia in CIPN animal model, and inhibition of TRPV4 resulted in attenuated mechanical allodynia (Hu et al. 2019). In a mouse model of paclitaxel-induced peripheral neuropathy (Matsumura et al. 2014), the expression of TRPV4 gene in paclitaxel-treated mice significantly increased compared with that in normal control mice and paclitaxel/Niuche Shenqi Wan-treated mice. There was no paclitaxel-induced mechanical hyperalgesia observed in TRPV4 knockout mice. It suggested that paclitaxel-induced hyperalgesia by enhancing TRPV4 expression, and Niuche Shenqi Wan might alleviate paclitaxel-induced hyperalgesia by suppressing TRPV4 expression in the dorsal root ganglions. In addition, in a rat model of paclitaxel-induced peripheral neuropathy, the prophylactic effect of puerarin, a major active ingredient of traditional Chinese plant medicine Gegen, was considered to be associated with the suppressed paclitaxel-induced transient receptor potential vanilloid 1 (TRPV1) in DRG (Wu et al. 2019b). The inhibitory effect on TRPV1 in DRG or in the spinal cord was also observed on cinobufacini (a water extract of the dried toad skin), quercetin (one of the polyphenolic flavonoid), and Corydalis saxicola Bunting total alkaloids in paclitaxel- or cisplatin-treated animals (Ba et al. 2018; Gao et al. 2016; Kuai et al. 2020).

Massive intracellular calcium accumulation has been implicated to play an important role in neuronal and tissue injury, and it has been documented as a key played in various neuropathic disorders (Muthuraman et al. 2008a, b; Sweitzer et al. 2006). In a rat model of vincristine-induced peripheral neuropathy, vincristine administration induced a significant rise in total calcium level in the sciatic nerve endings (Muthuraman and Singh 2011, Muthuraman et al. 2011). Pretreatment with hydroalcoholic extract of Acorus calamus attenuated the vincristine-evoked increase of total calcium level; the effect was similar with pregabalin treatment. The results indicated that Acorus calamus prevented vincristine-induced neuropathic pain, which may be attributed to its calcium inhibitory actions. The potential calcium inhibitory action may contribute to alleviating the effect on CIPN, which was also observed from Ocimum sanctum, Vernonia cinerea, Butea monosperma, as well as betulinic acid (derived from the desert lavender Hyptis emoryi), curcumin (Kaur et al. 2010; Thiagarajan et al. 2013, 2014; Bellampalli et al. 2019; Babu et al. 2015).

In addition, tetrodotoxin-sensitive voltage-dependent sodium channels have been demonstrated to attribute to the antinociceptive effect of (−)-hardwickiic acid and hautriwaic acid, the antinociceptive compounds from a library of natural products (Cai et al. 2019).

4.2.5 Regulating Endogenous Pain Modulation System

The endogenous cannabinoid system plays an important role in modulating pain sensation in the nociceptive pathway (Modesto-Lowe et al. 2018; Xu et al. 2020). The cannabinoid receptors, CB1 and CB2, are distributed throughout the peripheral and central nervous systems and in other organs and tissues. CB1 receptors are primarily found in the central nervous system, especially in regions implicated in conducting and modulating pain signals, including the periaqueductal gray and the spinal dorsal horn. CB2 receptors are found in peripheral tissues and organs, especially in those implicated in regulating immune function (Modesto-Lowe et al. 2018, Xu et al. 2020). Selective activation of CB2 receptors has been reported to suppress paclitaxel-induced peripheral neuropathic pain in rats (Rahn et al. 2008), and the prevention of CIPN was blocked by a CB2 antagonist (Naguib et al. 2012). In addition, CB1 receptor has also been demonstrated to attribute to the reduction of pain and neurotoxicity produced by chemotherapeutic agents (Khasabova et al. 2012). In a rat model of paclitaxel- or vincristine-induced peripheral neuropathy, activation of CB1 and CB2 receptors by nonselective CB1/CB2 receptor agonist WIN55,212 significantly reduced neuropathic pain induced by chemotherapeutic agents (Pascual et al. 2005; Rahn et al. 2007). Similarly, the mixed CB1/CB2 receptor agonist D⁹-tetrahydrocannabinol (THC), the major psychoactive ingredient in cannabis, attenuated paclitaxel- or vincristine-induced peripheral neuropathy in mice (King et al. 2017). Furthermore, low ineffective doses of cannabidiol combined with THC displayed a synergistic effect in preclinical researches.

Like the cannabinoid system, the endogenous opioid analgesic system is also located throughout the peripheral and central nervous system (Toubia and Khalife 2019; Gomes et al. 2020). It is comprised of a wide array of ligands and receptors, including κ-, δ-, and κ-receptor. It also plays an important role in modulating pain transmission. Exogenous therapy may affect the endogenous opioid system and alter its functions contributing to the regulation of pain sensation. Despite not in the same plant family as the opium poppy, kratom, a coffee-like plant, contains compounds that cause opioid and stimulant effects. Mitragynine, a bioactive alkaloid of kratom, significantly suppressed oxaliplatin-induced mechanical allodynia in rats (Foss et al. 2020). The anti-allodynic effect of mitragynine was completely blocked by opioid antagonist naltrexone, indicating the mitragynine reduced CIPN through opioid mechanism. In addition, adrenergic mechanism has also been demonstrated to attribute to the anti-allodynic effect of mitragynine (Foss et al. 2020).

Serotonin (5-hydroxytryptamine [5-HT]) is a widely distributed monoamine in the peripheral and central nervous systems. Serotonin and norepinephrine have been known to participate in the descending inhibitory nociception pathway and to play a pivotal role in opioid-mediated supraspinal analgesia (Zemlan et al. 1983; Hu et al. 2019). Recent data demonstrated that targeting serotonin and norepinephrine, such as serotonin/norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors, may be an efficient strategy in painful CIPN management (Hu et al. 2019). In a rat model of cisplatin-induced peripheral neuropathy, cisplatin caused low level of 5-HT in the spinal cord, whereas i.t. administration of red ginseng extract increased the 5-HT level in cisplatin-treated rats (Kim et al. 2020). Furthermore, the anti-allodynic effect of red ginseng extract can be blocked by i.t. administration of 5-HT receptor antagonist or 5-HT₇ receptor antagonist, indicating that spinal 5-HT₇ receptor may contribute to the anti-allodynic effect of red ginseng.

Dopaminergic neurotransmission has been demonstrated to play a pivotal role in modulating pain perception and natural analgesia (Wood 2008; Li et al. 2019a). In a mouse model of oxaliplatin-induced peripheral neuropathy, the anti-hyperalgesic effect of L-THP (the active component of Corydalis yanhusuo) was significantly blocked by a dopamine D1 receptor antagonist, indicating a dopamine D1 receptor mechanism attributes to its anti-hyperalgesic effect (Guo et al. 2014).

Calcitonin gene-related peptide (CGRP) and substance P (SP) are two important neurotransmitters demonstrated to attribute to neuropathic pain. Paclitaxel induced an increase of CGRP and SP in the dorsal root ganglia, whereas puerarin, a major active ingredient of traditional Chinese plant medicine Gegen, suppressed the upregulation of CGRP and SP (Wu et al. 2019b).

In addition, the excitatory neurotransmitters, l-glutamic acid and l-aspartic acid, were attenuated in the brain by saponins from Tribulus terrestris in a rat model of vincristine-induced peripheral neuropathy, implying the restoration of neuronal damage and synaptic activity and then reversing the nociceptive processing (Gautam and Ramanathan 2019).

4.2.6 Antitumor Activity

Several studies have been documented that herbal medicine, such as Huangqi Guizhi Wuwu Tang, Astragali radix, Lithospermi radix, and so on, alleviates chemotherapy-induced peripheral neuropathy without affecting the antitumor potential of chemotherapeutic drugs (Bahar et al. 2013, Ushio et al. 2012, Cho et al. 2016, Di Cesare Mannelli et al. 2017).

It has been determined that Huangqi Guizhi Wuwu Tang could reduce platinum intake in the DRG of rat treated with oxaliplatin and could promote platinum pumping, so as to reduce platinum accumulation and prevent oxaliplatin-induced chronic peripheral neurotoxicity (Gu et al. 2020). In a clinical study of 72 colorectal cancer patients, AC591 (a standardized extract of Huangqi Guizhi Wuwu Tang) prevented oxaliplatin-induced neuropathy, whereas the tumor response rate to chemotherapy has no significant difference between the patients with AC591 and without AC591 (Cheng et al. 2017). The in vivo and in vitro studies showed that Niuche Shenqi Wan did not affect the antitumor effect of oxaliplatin/paclitaxel in tumor cells or tumor cell-implanted animals (Bahar et al. 2013; Ushio et al. 2012). The 50% hydroalcoholic extract of Astragali radix relieved the oxaliplatin-induced pain, but it did not affect the oxaliplatin-induced apoptosis of colon tumor in a rat model of colon carcinogenesis (Di Cesare Mannelli et al. 2017).

In addition, metabolic disturbance of pathways of linoleic acid (LA) metabolism and glycerophospholipid metabolism has been reported in a rat model of paclitaxel-induced peripheral neuropathy (Wu et al. 2018). Wenluotong Tang has the ability to rebalance the metabolic disturbances by primarily regulating LA and glycerophospholipid metabolism pathway in paclitaxel rats.

4.3 Physical Exercise

Exercise has been proposed to protect against the development of a series of chronic disease, such as coronary heart disease, stroke, type 2 diabetes mellitus, etc., partially due to its anti-inflammatory actions, which may be mediated by a reduction in visceral fat mass with a subsequent decrease of proinflammatory adipokines (such as IL-6 and TNF) and by the induction of an anti-inflammatory environment (Gleeson et al. 2011). Physical exercise has also been found to regulate inflammation in patients receiving chemotherapy. In a randomized clinical trial, patients accepted 6 weeks of moderate-intensity walking and resistance exercise, which showed that exercise induced an anti-inflammatory cytokine profile per reduction in inflammatory cytokines in the serum (Kleckner et al. 2019). It may suggest that exercise reduces chemotherapy-induced peripheral neuropathy partly due to its anti-inflammatory effects.

Previous studies have shown that physical exercise improved peripheral nerve regeneration, increased both number of axons and rate of axonal elongation, and facilitated nerve rehabilitation from injury (Andersen Hammond et al. 2019). In a mouse model of paclitaxel-induced peripheral neuropathy, exercise prevented IENFs loss in hind paw and the reduction of myelinated axons in the sural nerve induced by paclitaxel, indicating the neuroprotective effect of exercise (Park et al. 2015). In an epidemiological research, the breast cancer survivors who did exercising (at least 30 minutes on most days) reported a 12% lower risk of peripheral neuropathy, indicating the possible neuroprotective role of exercise in CIPN (Mustafa Ali et al. 2017). Furthermore, exercise has been found to abrogate paclitaxel-induced reductions in cellular proliferation and to increase BrDu expression in the dentate gyrus of the hippocampus, indicating its neuroprotective effect and prompting neurogenesis (Slivicki et al. 2019). All these suggested the neuroprotective effect of exercise in CIPN. In addition, exercise is able to cause reorganization of brain functions (Holschneider et al. 2007) and to regulate endogenous opioid system (Stagg et al. 2011).

Moreover, exercise may reduce chemotherapy-induced peripheral neuropathy by improving physical functioning, increasing blood flow and supply of glucose and oxygen, improving sensorimotor function, regulating oxidative stress, regulating parasympathetic and sympathetic activities, and regulating endogenous pain and analgesic system (Coughlin et al. 2019; Stuecher et al. 2019; Kanzawa-Lee et al. 2020; Wilcoxon et al. 2020; Lin et al. 2021; Bao et al. 2020).

4.4 Other Complementary Therapies

The development of peripheral neuropathy has been reported to be associated with high blood concentrations of chemotherapeutic agents (Mielke et al. 2005; Chiorazzi et al. 2012; Sato et al. 2016). Cryotherapy is one of the nonpharmacological methods used to reduce peripheral exposure to chemotherapeutic agents in clinical practice. The application of frozen glove, cold insulators, or cold patches to the hand, wrist, or foot before, during, and after chemotherapy induced local vasoconstriction and reduced local blood supply, subsequently reduced peripheral exposure to chemotherapeutic agents, and decreased cellular uptake (Sato et al. 2016; Simsek and Demir 2021; Scotte et al. 2005; Sphar et al. 2020). On the other side, the regional cooling induced low cellular metabolism; reduced the release of vasodilator substances, the activity of biochemicals, and the sensitivity of nociceptor; and reduced muscle spasm by decreasing nerve conduction velocity and muscle excitability (Simsek and Demir 2021; Sphar et al. 2020).

On the contrary, the preventive effect of massage for chemotherapy-induced peripheral neuropathy may be due to the circulation-boosting effects of massage (Izgu et al. 2019a; Cunningham et al. 2011; Niemand et al. 2020). Massage stimulated vasomotor nerves resulting in local blood microcirculation, which may prevent the accumulation of neurotoxic substances caused by chemotherapy in the peripheral nervous system, and may increase blood supplies to the nervous system (Izgu et al. 2019a). In addition, massage affected the regulation of muscles, joints, tendons, and ligaments in the body (Izgu et al. 2019a). Massage at acupoints induced similar physiological effects to those of acupuncture (Samuels and Ben-Arye 2020). Foot massage, using reflexology, not only stimulates the reflex zones but also promotes blood circulation and induces relaxation (Park and Park 2015). Foot bathing promotes blood circulation by expanding the peripheral blood vessels (Park and Park 2015).

In addition, photobiomodulation therapy is supposed to stimulate tissue repair, reduce inflammation, promote nerve regeneration, and improve neural function (Argenta et al. 2017; Lodewijckx et al. 2020). However, much remains unknown despite great progress has been made in the biological mechanisms underlying the preventive and/or therapeutic effects of the integrative therapy in chemotherapy-induced peripheral neuropathy.

5 Conclusion Remarks

Currently, there are no established therapeutic strategies for the management of chemotherapy-induced peripheral neuropathy. The lack of effective CIPN therapeutics has boosted the demand for the use of alternative and complementary therapies. This chapter summarized the alternative and complementary therapies that were reported to be effective for CIPN management. We have found good and promising evidence on the efficacy of alternative and complementary therapies in improving CIPN symptoms in this chapter. These alternative and complementary therapies include acupuncture, medicinal herbs, exercise, cryotherapy, massage, and photobiomodulation. Generally, these therapies are multitargeted.

However, we did observe some heterogeneity from the available research publications; it might be due to the methodological differences among these therapeutic interventions of different studies. For example, the sample number, intervention time and duration, dosing parameters, criteria for efficacy evaluation, observing time window of the therapeutic effect, statistical method, and control group vary from different trials. Therefore, randomized controlled trials to define and refine the optimal treatment parameters and CIPN outcome measures are necessary to implement these therapies within a standard clinical setting. In addition, the mechanism underlying these therapies on CIPN is still lacking. Future studies should focus on animal models designed to reveal the working mechanisms being involved in these therapies.

With the increasing evidence from numerous studies on the alternative and complementary therapies in the management of chemotherapy-induced peripheral neuropathy, we believe that more and more cancer patients would benefit from the use of alternative and complementary therapies in CIPN management.